David Gadian – Using brain imaging to treat children

At the UCL Institute of Child Health, Professor David Gadian is working with clinicians including neurologists, cognitive neuroscientists and neurosurgeons to develop safe and non-invasive techniques to diagnose and aid treatment of brain disorders in children, Professor Gadian has been involved in advancing the medical possibilities of nuclear magnetic resonance techniques since they first began to be used in clinical settings. Penny Bailey spoke to him about his career and how physics is aiding medicine.

“As a physicist I’ve always been interested in applying the techniques of physics to solve important problems in biology and medicine,” says Professor David Gadian at the Institute of Child Health – the research arm of Great Ormond Street Hospital. To this end, he has spent the past three decades working closely with clinicians in hospitals to research and develop imaging techniques that improve the diagnosis and treatment of patients.

In the early 1980s, Professor Gadian set up a research group at the Royal College of Surgeons to explore biomedical applications of nuclear magnetic resonance (NMR). He had been one of the first people to use NMR to study tissue metabolism in the 1970s, and now he worked closely with researchers and clinicians at Hammersmith Hospital who were building the first clinically useful magnetic resonance imaging (MRI) systems.

“They showed how MRI could be used to show contrast in the brain – between grey and white matter, and between normal tissue and diseased tissue – and used that to build applications to detect tumours, multiple sclerosis, and other neurological disorders. It was pioneering work, remarkable at the time,” says Professor Gadian.

Professor David Gadian

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In 1990, he was recruited to set up another research group at the Institute of Child Health, aiming to develop NMR techniques that could be used safely and accurately in children. “The beauty of NMR for looking at tissue chemistry is that it’s completely safe and non-invasive. It doesn’t require any surgical manipulation or involve ionising radiation, so it’s safe to use in children,” he explains.

This was just at the time when MRI technology was starting to evolve rapidly. Scientists were able to make images of the brain within a period of seconds, rather than minutes, and could start looking at dynamic changes in the brain.

The technique known as functional MRI (fMRI) makes the water signal sensitive to whether the blood in the brain is oxygenated. Since the oxygenation state of the blood changes when a particular part of the brain is active (known as the blood oxygenation level dependent, or BOLD, response), fMRI provides a picture of which brain areas are active when people are performing a specific task or function.

Patient coming out of an MRI scanner with the brain scans on a computer screen in the foreground.

Professor Gadian and colleagues were among the first groups in the UK to show that fMRI was robust and accurate. They reported the first studies of using it to look at seizure activity (over-activation in certain parts of the brain) in 1994 (ref. 5), and have been at the forefront of research worldwide to establish these techniques for use in children with epilepsy.

“Epilepsy surgery can be hugely successful in the treatment of children who don’t respond to medication,” says Professor Gadian. However, surgeons faced with making a decision about whether to operate or not – and about the extent of surgery to perform – have understandable concerns about possibly damaging a part of the brain that might play a role in language, speech, cognition, movement, or any other vital function.

Professor Gadian and colleagues have been using fMRI and other imaging techniques to identify which parts of the brain are activated during certain tasks to help surgeons make those difficult decisions with greater precision. The techniques were recently incorporated as standard clinical practice in the epilepsy surgery programme at Great Ormond Street Hospital.

This remarkable cohesion of physics and medicine has been possible, says Professor Gadian, because he has been able to work right in the centre of the hospital, as part of a team alongside neurologists, cognitive neuroscientists and neurosurgeons, rather than separately, in a physics laboratory.

“‘If you’re a scientist, typically you do an experiment, then repeat and repeat it to show it’s reproducible, and then publish your results,” he says. “But as a clinician looking at a child with epilepsy, you have to make a decision about that particular child. Do you operate or not? You can’t say let’s look at a few more cases, or let’s repeat the experiment and see what happens.

“For me, the achievement has been seeing our findings translate into an improved outcome for an individual child. I think that unless you’re enmeshed actually within the clinical environment, as a scientist you don’t necessarily get that satisfaction.”

Tracing memory loss

Following on from Professor Gadian’s imaging studies of epilepsy and brain function, another important development has been the discovery of an entirely new condition that had not previously been recognised.

Epilepsy is often caused by damage to the hippocampus, a structure in the brain that is important for episodic memory (memory of events).

To understand more about this type of relationship between structure and function, Professor Gadian and colleagues began to unpick the brain structure-function relationships in groups of children with various forms of cognitive impairment, including children with epilepsy and children who had been born prematurely. Those studies revealed a small sub-group of children who all have a similar but an unusual form of memory loss, which the researchers termed ‘developmental amnesia’.

“These children have a profound loss of memory for events, but a surprisingly intact memory for facts,” says Professor Gadian. “A child might remember that Paris is the capital of France, for example, but not that he or she had been there on holiday.” Imaging studies showed that these children had suffered severe damage to the hippocampi in both hemispheres of the brain.

Oxygen deprivation

Follow-up work suggested that this form of damage could be linked to a loss of oxygen to the brain at some point in the child’s life – for example during birth – and this type of outcome came as a surprise to the medical and science professions.

“It’s known that oxygen deprivation can cause severe motor and cognitive impairments, but nobody seemed to be aware of the possibility that it might instead cause selective memory problems. We believe that in developmental amnesia the impairments in oxygen are insufficient to cause those major problems, but sufficient to cause the more selective memory problems that we saw.”

The work, carried out in collaboration with cognitive neuroscientist Faraneh Vargha-Khadem, also at the Institute of Child Health, and published in ‘Science’ (ref. 4) and ‘Brain’ (ref. 3), has attracted the attention of memory neuroscientists. This is partly because of the remarkable dissociation between the two types of memory, which characterises the condition, and partly it is caused by selective damage to a particular structure in the brain – the hippocampus.

He also hopes the children will benefit from this work. “What happens with these children is that at the age of five or six, they seem to be forgetful, at eight or nine, when they’re forgetting appointments or homework, it’s becoming naughty. But then as they get older, it’s seen as a sheer irresponsibility – an inability to take on the issues of every day life. So it’s very debilitating,” he says.

“If we can identify and diagnose the condition early on through brain imaging, that might help destigmatise the children suffering from it and might also suggest approaches to remediation.”

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